1. Field of the Invention
The invention relates to a method for the production of [4-(2,6-diamino-9H-purin-9-yl)-1,3-dioxolan-2-yl]methanol derivatives comprising a protective group R1 on the hydroxyl group (abbreviated below to hydroxyl protective group or “OH-protected”) of the general formula (1), where the radicals R8, R9, R10 and R11 are independently of one another hydrogen or an amino protective group.

2. Description of the Related Art
Nucleosides and nucleoside analogs represent an important class of substances having antiviral activity. Examples of nucleoside analogs showing activity against HIV are 3′-azido-3′-deoxythymidine (AZT) and 2′,3′-dideoxycytidine (ddC). Because of various effects, but especially because of the occurrence of resistances, more modern substances with a modified profile of action have been developed.
The nucleoside analogs which have proved to be particularly advantageous are those comprising a 1,3-oxathiolane ring such as, for example, lamivudine (3TC) and coviracil (FTC) or a 1,3-dioxolane ring such as [(2R,4R)-[4-(2,6-diamino-9H-purin-9-yl)-1,3-dioxolan-2-yl]methanol (abbreviated below to “(−)-DAPD”).
The synthesis of such nucleoside analogs by reacting the nucleobase or its synthetic precursor with the sugar unit in the presence of a Lewis acid now represents a standard reaction known in the art. If a silylated nucleobase is used therein, the reaction is known as the “silyl Hilbert-Johnson reaction” [H. Vorbrüggen, G. Hoefle, Chem. Ber. 1981, 114, 1256-1268].
Lewis acids frequently used, in addition to metal halides and alcoholates, and transition metal halides and alcoholates such as SnCl4, TiCl4 or TiCl2(OiPr)2, are silyl derivatives of perfluoro sulfonic acids such as trimethylsilyl trifluoromethanesulfonate or triakylsilyl halides such as iodotrimethylsilane.
It is assumed that the mechanism in the case of ribose derivatives (i.e. 2′-substituted sugar units) involves the formation of a cation from the sugar unit comprising a leaving group in position 1′, for example, acetate, by the neighboring group effect under the influence of the Lewis acid, the cation reacting in the second step with the silylated nucleobase. In the case of silyl halides such as iodotrimethylsilane, WO 01/58894 postulates initial replacement of the leaving group by halide, for example, iodide. The iodine compound which is formed is then reacted with the silylated nucleobase.
Nucleoside analogs comprising 2,6-diaminopurine as base are normally synthesized by initially introducing 2,6-dichloropurine or 2-amino-6-chloropurine as base precursor, and the chlorine atom(s) being converted into amino groups in a later step. This can take place directly by reaction with ammonia or in two steps by reaction with azide to give the diazida derivative and subsequent catalytic hydrogenation to give the diamino derivative. The direct reaction with ammonia takes place only poorly to afford very low yields. The azide variant has the disadvantage that two reaction steps are necessary. The great disadvantage of both methods is, however, that the use of the very costly 2,6-dichloropurine or 2-amino-6-chloropurine makes the reaction economically uninteresting. In addition, because of the higher molecular weights of the precursors it is necessary to employ in the described reaction variants about 1.25 kg of dichloropurine or 1.13 kg of aminochloropurine instead of 1 kg of diaminopurine (assuming identical yields).
WO 97/21706 describes a method for producing β-nucleoside analogs having a 1,3-dioxolane ring, where a purine or pyrimidine base is reacted at temperatures below −10° C. with a 1,3-dioxolane unit which comprises a halogen atom as leaving group. The dioxolane unit is in this case preferably prepared from the corresponding acetoxy derivative by reaction with iodotrimethylsilane or diiodosilane.
Reference is made in this connection in particular to the high stereoselection when carried out at low temperatures. This method has the disadvantage that it relies on low-temperature reactions, since particularly high stereoselectivities (β:α isomer ratio) are described at a reaction temperature of −78° C.
Use of 2,6-diaminopurine as base in this method results in only poor yields or numerous byproducts (cf. Comparative Example 5). In addition, because of the low reactivity of diaminopurine, the low reaction temperatures which are, according to the teaching of WO 97/21706, necessary to achieve high stereoselectivities are a great technical disadvantage of the method because they necessitate very long reaction times (>24 h).
WO 01/58894 describes the production of DAPD and its enantiomers by applying the method disclosed in WO 97/21706 to the reaction of 4-acetoxy-2-benzoyloxymethyl-1,3-dioxolane with 2-amino-6-chloropurine (carried out at −15° C.). The product which has been purified by column chromatography and has a β:α isomer ratio of 2.3:1 is then converted by reaction with methanolic ammonia and subsequent column chromatography into DAPD with a β:α isomer ratio of 2:1. The disadvantage here is once again the use of costly 2-amino-6-chloropurine and the repeated employment of column chromatography.